Project 2: Opioids are known to have multiple effects on the immune system. The goal of this project is to determine whether administration of them might accelerate the course of lentiviral disease progression. To do so, we propose an experiment of relatively simple design: infection of either pigtailed macaques (PT) or of African green monkeys (AGM) with the same isolate of SIVagm, in the presence or absence of morphine. Our preliminary data and those of others indicate that, after SIVagm infection, the former species (PT) develops signs of progressive disease whereas the latter species (AGM) does not. We hypothesize that: (a) if certain "protective" innate and/or adaptive immune responses play a role in suppressing SIV-induced pathology in the AGM, and if morphine administration interferes with these responses, then a non-pathogenic infection may be converted into one that is pathogenic;and, contrariwise (b) if certain innate and/or adaptive immune responses play a role in accelerating SIV-induced pathology in the PT (e.g., by inducing inflammation and chronic immune activation), and if morphine administration interferes with these responses, then a pathogenic infection may be converted into one that is non-pathogenic. To test these hypotheses, four groups of three animals each, including two groups of AGMs and two groups of PTs, will be challenged intravenously with SIVagm and then followed longitudinally for 60 days, treated or not with morphine (starting 10 days prior to infection and continuing throughout the 60 day period post-infection). During this time frame, samples of peripheral blood, lymph node, colon, and cerebrospinal fluid will be obtained and studied for proteomic, immunologic, virologic, and functional genomic bio-signatures. Data from these analyses will then be evaluated to address the following Specific Aims: (1) to define the proteomic signatures that are associated with pathogenic and non-pathogenic SIV infection of non-human primates;(2) to determine the effect of opioids on the immune system of uninfected non-human primates;and (3) to determine the effect of opioids on disease progression in SIV-infected non-human primates.